A major advance in our understanding of acid-base homeostasis and ammonia metabolism is the identification that Rh glycoproteins are ammonia transporters. In the kidney, published data and our preliminary data indicates that Rh glycoprotein B Glycoprotein (Rhbg) mediates a previously unrecognized role in renal ammonia metabolism. A second advance has been the recognition that Rhbg is expressed in principal cells, a cell not generally known to be involved in acid-base homeostasis, and that adaptive changes in principal cell Rhbg may be an important component of the renal response to metabolic acidosis. Thus, the overall aim of this application is to determine Rhbg's role in acid-base homeostasis and in potassium homeostasis. The first goal is to determine the specific role of Rhbg in the renal response to metabolic acidosis. We will use Cre-loxP technology to generate transgenic mice with kidney-specific, intercalated cell-specific and principal cell-specific Rhbg deletion. We will also generate mice with kidney-specific Rhbg and Rhcg deletion. We will then examine acid-base homeostasis in these mice under control conditions and in response to metabolic acidosis in order to determine the specific role of Rhcg in renal acid-base homeostasis, and the specific contributions of intercalated cells and principal cells to acid-base homeostasis. Our second aim is to determine Rhbg's specific role in the renal response to hypokalemia. We will again use Cre-loxP technology to generate transgenic mice with kidney-specific, intercalated cell-specific and principal cell-specific Rhbg deletion. We will then examine acid-base and potassium homeostasis in these mice under control conditions and in response to dietary potassium deficiency in order to determine Rhbg's role in the renal response to hypokalemia, and the specific contributions of intercalated cells and principal cells to Rhbg-mediated ion transport in response to hypokalemia. PUBLIC HEALTH RELEVANCE: Acid-base disorders are common in veterans, and are associated with osteoporosis, muscle atrophy, growth retardation, renal stone disease and increased morbidity. They may also contribute to the progression of chronic kidney disease. The proposed studies will provide new insights into mechanisms of acid-base homeostasis, and thereby provide the necessary underpinnings for new and novel treatments for veterans with acid-base disorders.